Trials@uspto.gov Paper 166 571-272-7822 Entered: September 2, 2014

UNITED STATES PATENT AND TRADEMARK OFFICE ____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

____________________

ARIOSA DIAGNOSTICS, Petitioner,

v.

ISIS INNOVATION LIMITED, Patent Owner.

____________________

Case IPR2012-000221 Patent 6,258,540

___________________

Before LORA M. GREEN, FRANCISCO C. PRATS, and JEFFREY B. ROBERTSON, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

FINAL WRITTEN DECISION 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73

I. INTRODUCTION

A. Background

Petitioner, Ariosa Diagnostics (“Ariosa”), filed a Petition for inter

partes review of claims 1, 2, 4, 5, 8, 19–22, 24, and 25 of U.S. Patent No.

6,258,540 (“the ’540 Patent”) pursuant to 35 U.S.C. §§ 311–319. Paper 1

(“Pet.”). Patent Owner, Isis Innovation Limited (“Isis”), filed a Preliminary 1 This Case has been joined with IPR2013-00250.

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Response. Paper 18 (“Prelim. Resp.”). On March 19, 2013, we instituted

trial as to all of the challenged claims. Paper 24 (“Dec. Institute”).

After institution of trial in IPR2012-00022, Ariosa filed a second

Petition for inter partes review of claims 3, 8, 12, 13, 15, and 18 of the ’540

patent. IPR2013-00250, Paper 1. Ariosa also filed a Motion for Joinder,

seeking joinder of that proceeding with IPR2012-00022. IPR2013-00250,

Paper 4. On September 3, 2013, we instituted trial as to all of the claims

challenged in the second Petition (IPR2013-00250, Paper 26), and joined the

proceeding with IPR2012-00022 (IPR2013-00250, Paper 25). Thus, claims

1–5, 8, 12, 13, 15, 18–22, 24, and 25 are subject to inter partes review in the

joined proceeding.

Isis filed a Patent Owner Response in the joined proceeding. Paper 89

(“PO Resp.”). Isis filed also a contingent Motion to Amend by submitting

proposed substitute new claims 28–30, or substitute new claims 31–33, for

claims 1, 24, and 25, respectively. Paper 88 (“Mot. to Amend”). Ariosa

filed a Reply to the Patent Owner Response (Paper 114; “Reply”), and also

an opposition to Isis’s Motion to Amend (Paper 115; “Opp.”). Isis then filed

a Reply in support of its Motion to Amend. Paper 130 (“Reply Mot. to

Amend”).

Isis filed a Motion to Exclude. (Paper 135; “Isis’s Motion to

Exclude”); and Ariosa filed an Opposition to that Motion (Paper 155). Oral

hearing was held on January 24, 2014. Paper 1652 (“Tr.).

2 We note that the pages of the oral hearing transcript are not numbered. We, thus, designate the first page on which argument appeared, entitled “PROCEEDINGS,” as page 1, and number the remaining pages sequentially therefrom.

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The Board has jurisdiction under 35 U.S.C. § 6(c). This Final Written

Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.

Ariosa has demonstrated, by a preponderance of the evidence of

record, the unpatentability of claims 1, 2, 4, 5, 8, 19, 20, 24, and 25 under 35

U.S.C. § 102(b). Ariosa, however, has not met its burden to show by a

preponderance of the evidence of record that claims 3, 12, 13, 15, 18, 21,

and 22 are unpatentable under 35 US.C. § 103(a).

Isis’s Motion to Amend is denied.

B. Related Proceedings

Claims 1, 2, 4, 5, 8, 19–22, 24, and 25 of the ’540 patent were

declared invalid in Ariosa Diagnostics v. Sequenom, Civ. No. 12-00132-SI

(N.D. Cal.). Paper 107, 1 (citing Ex. 2224). The district court granted

summary judgment on the basis that the claims were drawn to patent

ineligible subject matter under 35 U.S.C. § 101. Ex. 2224, 20. The district

court’s decision is currently on appeal to the Court of Appeals for the

Federal Circuit in Ariosa Diagnostics, Inc. v. Sequenom, Inc., Appeal Nos.

14-1139, 14-1142, and 14-1144. Paper 163, 1.

C. The ’540 Patent

The ’540 patent issued on July 10, 2001, with Yuk-Ming Dennis Lo

and James Stephen Wainscoat as the listed co-inventors. The ’540 patent is

drawn to “prenatal detection methods using non-invasive techniques,” and,

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in particular, “to prenatal diagnosis by detecting foetal nucleic acids in

serum or plasma from a maternal blood sample.” Ex. 1001,3 col. 1, ll. 6–9.

According to the ’540 patent, it was unexpected that fetal DNA “is

detectable in maternal serum or plasma samples.” Id. at col. 1, ll. 50–51.

The concentration of fetal DNA in serum or plasma samples has been

measured from 0.39% (early pregnancy) to 11.4% (late pregnancy), whereas

the concentration of fetal cells in the cellular fraction is generally from

0.001% to 0.025%. Id. at col. 1, ll. 59–64. The ’540 patent thus “provides a

detection method performed on a maternal serum or plasma sample from a

pregnant female, which method comprises detecting the presence of nucleic

acid of foetal origin in the sample.” Id. at col. 2, ll. 1–4. “[P]renatal

diagnosis” is defined by the ’540 patent as covering the “determination of

any maternal or foetal condition or characteristic which is related to either

the foetal DNA itself or to the quantity or quality of the foetal DNA in the

maternal serum or plasma.” Id. at col. 2, ll. 6–10.

The ’540 patent also teaches that the “preparation of serum or plasma

from the maternal blood sample is carried out by standard techniques,” and

that “[s]tandard nucleic acid amplification systems can be used.” Id. at col.

2, ll. 26–27 and ll. 43–47. Polymerase chain reaction (“PCR”) is one of the

standard nucleic acid amplification systems disclosed by the ’540 patent. Id.

at col. 2, ll. 44–48. According to the ’540 patent, “[s]ex determination has

successfully been performed on pregnancies from 7 to 40 weeks of

gestation.” Id. at col. 3, ll. 60–62.

3 Throughout the decision, quotations to the ’540 patent (Ex. 1001) include the British spelling of several words. We, otherwise, use the American spelling; for example, “foetal” versus “fetal.”

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The ’540 patent teaches further that the plasma or serum-based

prenatal diagnostic method may be used to determine fetal rhesus D status in

rhesus negative mothers, such that the detection of the rhesus D gene in the

negative mother is indicative of a rhesus D positive fetus. Id. at col. 2, l. 57–

col. 3, l. 3. The diagnostic methods may be used also to detect

haemoglobinopathies or other paternally-inherited DNA polymorphisms. Id.

at col. 3, ll. 4–24.

According to the ’540 patent, the non-invasive methods may be used

also to screen for Down’s syndrome and other chromosomal aneuploidies.

Id. at col. 3, ll. 25–28. The ’540 patent teaches that it was known that the

level of circulating fetal cells is higher in pregnancies with chromosomal

aneuploidies, such as Down’s syndrome, and it was further determined that

the level of fetal DNA in maternal plasma and serum is also higher. Id. at

col. 3, ll. 30–40. Thus, the ’540 patent teaches that quantitative detection of

fetal DNA in maternal plasma or serum may be used to screen for fetal

aneuploidies. Id. at col. 3, ll. 40–43. Another method disclosed by the ’540

patent for use in screening fetal aneuploidies is quantifying fetal DNA

markers on different chromosomes, such as quantification of fetal

chromosomal 21-derived DNA. Id. at col. 3, ll. 44–51.

Example 2 of the ’540 patent describes quantitative analysis of fetal

DNA in maternal serum, wherein the pregnancy is an aneuploidy pregnancy.

Id. at col. 5, ll. 55–57. Plasma and serum samples were obtained from

pregnant women undergoing prenatal testing, and DNA was extracted from

those samples. Id. at col. 6, ll. 14–34. The DNA then was amplified using

real time quantitative PCR using primers for the SRY gene. Id. at col. 6,

l. 35–col. 7, l. 3. The inventors report that the concentration of fetal DNA is

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elevated in aneuploid pregnancies. Id. at col. 8, ll. 33–36. The same test,

using the same primers, was used to screen for pre-eclampsia, wherein the

concentration of fetal DNA is higher in patients with pre-eclamptic

pregnancies. Id. at col. 11, l. 38–col. 12, l. 49, Example 4.

The SRY gene is male specific, being found on the Y chromosome.

Id. at col. 25, ll. 6–7, claim 7. The ’540 patent teaches that the “[r]eal time

quantitative SRY system was insensitive to the existence of background

female DNA from 0 to 12,800 female genome-equivalents.” Id. at col. 14,

ll. 46–48. In addition, samples from women bearing female fetuses did not

provide a positive SRY signal. Id. at col. 15, ll. 63–67.

According to the ’540 patent,

For selected disorders, foetal genetic information could be acquired more economically and rapidly from maternal plasma or serum than by using foetal cells isolated from maternal blood. We envisage that foetal DNA analysis in maternal plasma and serum would be most useful in situations where the determination of foetal-derived paternally inherited polymorphisms/mutations or genes would be helpful in clinical prenatal diagnosis. Examples include foetal sex determination for the prenatal diagnosis of sex-linked disorders, foetal rhesus D status determination in sensitized rhesus negative pregnant women, autosomal dominant disorders in which the father carries the mutation and autosomal recessive genetic disorders in which the father and mother carry different mutations, e.g., certain hemoglobinopathies and cystic fibrosis. Due to the much reduced maternal background and high foetal DNA concentration in maternal plasma and serum, we predict that this type of analysis would be much more robust compared with their application for detecting unsorted foetal cells in maternal blood. The ability for allelic discrimination allows the homogeneous TaqMan assay to be used for this purpose.

Id. at col. 17, ll. 32–54 (citations omitted).

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As for the application of the method to female fetuses, the ’540 patent

teaches:

[I]t has been demonstrated (Example 2) that the foetal DNA concentration in maternal plasma and serum is . . . elevated in [aneuploid] pregnancies. This provides a new screening test for foetal chromosomal disorders. For this application, foetal DNA quantitation systems can be developed for polymorphic markers outside the Y chromosome so that quantitation can be applied to female foetuses. Autosomal polymorphic systems which may be used for this purpose have already been described. However, foetal cell isolation techniques would still be necessary for a definitive cytogenetic diagnosis. Similarly, foetal cell isolation would also be required for direct mutational analysis of autosomal recessive disorders caused by a single mutation. It is likely that foetal cell isolation and analysis of foetal DNA in maternal plasma/serum would be used as complementary techniques for non-invasive prenatal diagnosis.

Id. at col. 17, l. 59–col. 18, l. 8 (citations omitted).

D. Illustrative Claim

Claims 1, 21, 24, and 25 of the ’540 patent are independent. Claim 1

is illustrative, and is reproduced below:

1. A method for detecting a paternally inherited nucleic acid of fetal origin performed on a maternal serum or plasma sample from a pregnant female, which method comprises amplifying a paternally inherited nucleic acid from the serum or plasma sample and detecting the presence of a paternally inherited nucleic acid of fetal origin in the sample.

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E. Instituted Challenges

Claims Basis References 1–5, 12, 13, 15, 18–22, 24, and 25 § 102(a) Lo

4

8 § 103(a) Lo and Simpson5

1, 2, 4, 5, 8, 19, 20, 24, and 25 § 102(b) Kazakov

6

3, 12, 13, 15, and 18 § 103(a) Kazakov and Bianchi7

1, 2, 4, 5, 19–22, 24, and 25 § 103(a)

Simpson, Schallhammer,8 and Kazakov

3, 12, 13, 15, and 18 § 103(a) Simpson, Schallhammer, Kazakov, and Bianchi

In regard to the challenge of claims 1–5, 12, 13, 15, 18–22, 24,

and 25 as being anticipated under 35 U.S.C. § 102(a) by Lo, as well as

the challenge of claim 8 as being rendered obvious under 35 U.S.C.

§ 103(a) over the combination of Lo and Simpson, we note that

Ariosa stated during oral argument that it is no longer pursuing those

challenges. Tr., 10:9–20. Without a further developed record, we

decline to address those challenges further in this Decision. 4 Lo et al., Presence of Fetal DNA in Maternal Plasma and Serum, 350 LANCET 485–487 (1997) (Ex. 1016). 5 Simpson et al., Isolating Fetal Cells in Maternal Circulation for Prenatal Diagnosis, 14 PRENATAL DIAGNOSIS 1229–1242 (1994) (Ex. 1025). 6 Kazakov et al., Extracellular DNA in the Blood of Pregnant Women, 37(3) CYTOLOGY (TSITOLOGIA) 232–236 (1995) (Ex. 1014). 7 Bianchi et al., Fetal Cells in Maternal Blood: Determination of Purity and Yield by Quantitative Polymerase Chain Reaction, 171 AM. J. OBST. GYNECOL. 922–26 (1994) (Ex. 1043). 8 Schallhammer et al., Phenotypic Comparison of Natural Killer Cells from Peripheral Blood and from Early Pregnancy Decidua, 3 EARLY PREGNANCY: BIOLOGY AND MEDICINE 15–22 (1997) (Ex. 1022).

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II. ANALYSIS

A. 35 U.S.C. § 315(a)(1)

Isis argues that Ariosa lacks standing on the basis of Ariosa’s filing of

a civil action challenging the validity of the ’540 patent before filing of the

Petition for Inter Partes Review. PO Resp. 59 (citing IPR2012-00022,

Prelim. Resp.). In the Preliminary Response, Isis asserted that Ariosa, prior

to filing its Petition, filed a civil action against Sequenom, the exclusive

licensee of the ’540 patent, seeking a declaration that it did not infringe any

claim of the ’540 patent. Prelim. Resp. 3–4. Sequenom counterclaimed for

infringement, and Ariosa answered by raising the affirmative defense of

invalidity of the ’540 patent. Id. at 4. We responded to that argument before

institution of the IPR2021-00022 proceeding. See generally Paper 20. As

this proceeding is at Final Decision, we summarize our Decision that

addressed the issue of whether Ariosa lacked standing to bring to bring the

IPR2012-00022 proceeding under 35 U.S.C. § 315(a)(1).

Specifically, in its Preliminary Response in IPR2012-00022, Isis

argued that it “is of no moment” that Ariosa’s challenge of the validity of the

’540 patent in civil litigation is in the form of an affirmative defense.

Prelim. Resp. 6. Isis asserted that the bar in § 315 does not require that the

challenge be placed in the complaint, but “is directed to a petitioner-initiated

‘civil action’—in other words the entire civil lawsuit—that challenges patent

validity.” Id. at 6–7.

Isis argued further that the exception in § 315(a)(3) does not apply, as

that exception is limited to a counterclaim. Id. at 7. According to Isis,

Ariosa only could have brought a counterclaim for invalidity if Isis and

Sequenom had initiated the civil action. Id. Isis cited Leatherman v.

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Tarrant County Narcotics Intelligence & Coordination Unit, 507 U.S. 163,

168 (U.S. 1993) (“Expressio unius est exclusio alterius”) for the “canon of

statutory interpretation ‘the express mention of one thing excludes all

others,’” arguing that canon excludes additional exceptions, such as the

filing of an affirmative defense of patent invalidity. Id. at 7–8.

Isis also asserted that to allow Ariosa to file an inter partes review

proceeding would thwart the intent of Congress. Id. at 5–6. According to

Isis, § 315 was enacted to “avoid patent-owner harassment and to further the

central purpose of IPRs to provide a cost-effective alternative to district-

court patent validity litigation.” Id. at 5. Thus, Isis asserted, a “key

directive” of the statute is that the party that wishes to challenge the validity

of a patent “must choose a single forum,” with the only narrow exception

being if the challenge is in the form of a counterclaim in a patent owner-

initiated civil action. Id. at 5–6.

The issue we thus addressed before instituting inter partes review in

IPR2012-00022 was

whether filing a Declaratory Judgment of non-infringement in District Court bars Ariosa from later filing a petition for Inter Partes Review under 35 U.S.C. § 315(a), and whether the express mention of a counterclaim of invalidity in 35 U.S.C. § 315(a)(3) mandates interpreting the statute such that raising an affirmative defense of invalidity in response to a compulsory counterclaim of infringement deprives Ariosa of standing to file for inter partes review.

Paper 20, 3–4.

We noted in our Decision that statutory construction “‘begins with

‘the language of the statute.’ And where the statutory language provides a

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clear answer, it ends there as well.’” Id. at 4 (quoting Hughes Aircraft Co. v.

Jacobson, 525 U.S. 432, 438 (1999) (citations omitted)).

“Beyond the statute’s text, [the ‘traditional tools of statutory construction’] include the statute’s structure, canons of statutory construction, and legislative history.” Timex V.I. v. United States, 157 F.3d 879, 882 (Fed.Cir.1998) (quoting Chevron U.S.A., Inc. v. Natural Res. Def. Council, Inc., 467 U.S. 837, 843 n. 9, 104 S.Ct. 2778, 81 L.Ed.2d 694 (1984)). “If a court, employing traditional tools of statutory construction, ascertains that Congress had an intention on the precise question at issue, that intention is the law and must be given effect,” Chevron, 467 U.S. at 843 n. 9, 104 S.Ct. 2778.

Bull v. U.S., 479 F.3d 1365, 1376 (Fed. Cir. 2007).

We first addressed the issue of what is meant by “the petitioner or real

party in interest filed a civil action challenging the validity of a claim of the

patent” in § 315(a)(1) of the statute. Paper 20, 4. Under Isis’s interpretation

of the statute, “filing” extends beyond the commencement of the civil action

and includes raising the affirmative defense of invalidity. Id. We looked to

the Federal Rules of Civil Procedure as a guide to interpreting the plain

meaning of the statute. Id.

We noted that Rule 2 of the Federal Rules of Civil Procedure9 states

that “[t]here is one form of action—the civil action,” and Rule 3 states that

“[a] civil action is commenced by filing a complaint with the court.” Id. at

5. Defenses are raised in answer to the complaint or in answer to a

counterclaim. Id. (citing Fed. R. Civ. P. 12). We concluded, therefore, that

when the statute refers to filing a civil action, it refers to filing a complaint

with the court to commence the civil action. Id.; see, e.g., Baldwin Cnty.

Welcome Ctr. v. Brown, 466 U.S. 147, 149 (1984) (citing Fed. R. Civ. P. 3 9 As amended December 1, 2010.

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for the proposition that a civil action is brought upon the filing of a

complaint with the court).

The next issue we addressed was whether the above interpretation of

what constitutes filing a civil action for purposes of § 315(a)(1) can be

reconciled with the explicit exception of filing a counterclaim for invalidity

in § 315(a)(3). Paper 20, 5.

In our Decision addressing this issue, we noted that the Supreme

Court has distinguished an affirmative defense of invalidity from a

counterclaim of invalidity in Cardinal Chem. Co. v. Morton Int’l, Inc., 508

U.S. 83 (1993). Paper 20, 5–6. The question before the Court in that case

was whether the Court of Appeals for the Federal Circuit properly vacated a

declaratory judgment of invalidity after finding that there was no

infringement. Cardinal Chem., 508 U.S. at 85. Quoting Altvater v.

Freeman, 319 U.S. 359, 363–364 (1943), the Court stated:

“To hold a patent valid if it is not infringed is to decide a hypothetical case. But the situation in the present case is quite different. We have here not only bill and answer but a counterclaim. Though the decision of non-infringement disposes of the bill and answer, it does not dispose of the counterclaim which raises the question of validity . . . . [T]he issue of validity may be raised by a counterclaim in an infringement suit. The requirements of case or controversy are of course no less strict under the Declaratory Judgments Act (48 Stat. 955, 28 U.S.C. § 400) than in case of other suits. But we are of the view that the issues raised by the present counterclaim were justiciable and that the controversy between the parties did not come to an end on the dismissal of the bill for non-infringement, since their dispute went beyond the single claim and the particular accused devices involved in that suit.”

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Cardinal Chem. Co., 508 U.S. at 94. The Court noted, however, that

Altvater did not answer the question of whether, in the absence of an

ongoing infringement dispute between the parties, an adjudication of

invalidity would be moot. Id. at 95.

In answering that question, the Court observed that “[a] party seeking

a declaratory judgment of invalidity presents a claim independent of the

patentee’s charge of infringement.” Id. at 96. The Court also emphasized

that there are public policy reasons to resolve questions of patent validity.

Id. at 100–101. The Court, thus, rejected the Federal Circuit’s practice of

vacating a declaratory judgment of invalidity after a finding of

noninfringement. Id. at 102.

Thus, it is clear from Cardinal Chem. Co. that there is a fundamental

difference between an affirmative defense of invalidity and a counterclaim

of invalidity. The affirmative defense of invalidity is tied to the claim of

infringement, whereas a counterclaim of invalidity is independent from the

claim of infringement and survives a finding of noninfringement. Section

315(a)(3) makes clear that if a party is faced with a claim of infringement, it

can bring the independent claim of invalidity as a counterclaim and still

avail itself of inter partes review.

Given the above analysis as a backdrop, we concluded that the

statutory language provides a clear answer to the issue of whether filing a

civil action for a declaratory judgment of noninfringement by a party

deprives that party of standing to file an inter partes review as a result of

raising the affirmative defense of invalidity in response to a counterclaim of

infringement. Paper 20, 6.

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As discussed above, the statute clearly defines which civil actions,

when filed, bar a party from filing an inter partes review—civil actions

challenging the validity of a patent. A civil action for a declaratory

judgment of non-infringement is not a civil action challenging the validity of

a patent. Moreover, as discussed above, asserting an affirmative defense of

invalidity is treated differently than a counterclaim for invalidity, and thus

for the purposes of § 315(a)(1) cannot be considered a filing of a civil action

for invalidity. And as also discussed above, that interpretation of

§ 315(a)(1) does not conflict with the explicit exclusion in § 315(a)(3) of

filing a counterclaim for invalidity.

We considered Isis’s argument that to allow Ariosa to file a

declaratory judgment action for noninfringement and also file a Petition for

inter partes review allows Ariosa to thwart the intent of Congress, but it did

not convince us otherwise.

In reviewing the legislative history of the America Invents Act10

(“AIA”) (Paper 20, 7–8), we noted that Senator Kyl stated in discussing the

Act:

Another set of changes made by the House bill concerns the coordination of inter partes and postgrant review with civil litigation. The Senate bill, at proposed sections 315(a) and 325(a), would have barred a party or his real party in interest from seeking or maintaining an inter partes or postgrant review after he has filed a declaratory-judgment action challenging the validity of the patent. The final bill will still bar seeking IPR or PGR after a declaratory-judgment action has been filed, but will allow a declaratory-judgment action to be filed on the same day or after the petition for IPR or PGR was filed. Such a declaratory-judgment action, however, will be automatically

10 Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284 (2011).

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stayed by the court unless the patent owner countersues for infringement. The purpose of allowing the declaratory-judgment action to be filed is to allow the accused infringer to file the first action and thus be presumptively entitled to his choice of venue.

157 Cong. Rec. S5429 (daily ed. Sept. 8, 2011)).

Thus, as made clear by Senator Kyl, § 315(a) was amended to allow a

petitioner to file an inter partes review, and still have a choice of venue by

allowing the petitioner to file a declaratory judgment action that same day.

Moreover, a party cannot bring a declaratory judgment action of

noninfringement without any basis for doing so.

Although there is no bright line rule to determine whether a declaratory judgment action satisfies Article III’s case-or-controversy requirements, the dispute must be “definite and concrete, touching the legal relations of parties having adverse legal interests,” “real and substantial,” and “admi[t] of specific relief through a decree of a conclusive character, as distinguished from an opinion advising what the law would be upon a hypothetical state of facts.” “Basically, the question in each case is whether the facts alleged, under all the circumstances, show that there is a substantial controversy, between parties having adverse legal interests, of sufficient immediacy and reality to warrant the issuance of a declaratory judgment.” Id..

3M Co. v. Avery Dennison Corp., 673 F.3d 1372, 1376 (Fed. Cir. 2012)

(citations omitted). And even when there is a case or controversy, the

district court still has discretion in deciding whether it will entertain the

declaratory judgment action. Id.

We concluded, therefore, that allowing a party to file both a

declaratory judgment action for noninfringement and an inter partes review

does not constitute harassment of a patent owner, because in order to bring

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the declaratory judgment action for noninfringement, a party must still

satisfy Article III’s case-or-controversy requirements. Paper 20, 8.

We, thus, concluded that 35 U.S.C. § 315(a) does not deprive Ariosa

of standing to bring the instant inter partes review. Id.

B. 35 U.S.C. § 315(b)

Isis argues further that this inter partes review is barred under

35 U.S.C. § 315(b). PO Resp. 59 (citing IPR2013-00250, Prelim. Resp.). In

its Preliminary Response filed in IPR2013-00250, Isis contended that under

35 U.S.C. § 315(b), the “Office may not institute inter partes review if the

petitioner filed its petition more than one year after being served with a

complaint alleging infringement of the patent.” IPR2013-00250, Prelim.

Resp. 42. According to Isis, Aria Diagnostics, Inc., now Ariosa, accepted

service of a complaint alleging infringement of the ’540 patent, more than a

year before the IPR2013-00250 Petition filing date of April 19, 2013. Id.

Isis acknowledged that the parties later agreed to dismissal of the civil

action without prejudice. Id. Isis argued, however, that § 315(b) leaves no

room for discretion, as it states that “inter partes review ‘may not be

instituted if the petition requesting the proceeding is filed more than 1 year

after the date on which the petitioner . . . is served with [the] complaint’” Id.

(alteration in original). According to Isis, the fact that the infringement suit

was dismissed without prejudice was immaterial to whether or not Ariosa

was barred from bringing the instant inter partes review against Isis. Id. at

42–44.

In the Decision to Institute in IPR2013-00250, we noted that that

argument had already been considered by the Board in Macauto U.S.A. v.

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BOS GMBH & KG, Case IPR2012-00004 (PTAB January 24, 2013) (Paper

18). IPR2013-00250, Paper 26, 4. In that proceeding, the panel noted that

the bar of filing an inter partes review under 35 U.S.C. § 315(b) did not

attach to a complaint of infringement that was voluntarily dismissed without

prejudice. See Macauto, slip. op. at 14–16. We agree with that reasoning,

discussed below.

Specifically, the panel in that case looked to the Federal Rules of Civil

Procedure in making its determination. Id. at 15. As to the requirement of

service, the panel noted that the infringement suit was voluntarily dismissed

without prejudice under Fed. R. Civ. P. 41(a). Id. The panel noted further

that the Court of Appeals for the Federal Circuit has consistently interpreted

the effect of such dismissals as leaving the parties as though the action had

never been brought. Id. (citing Graves v. Principi, 294 F.3d 1350, 1356

(Fed. Cir. 2002) (“The dismissal of an action without prejudice leaves the

parties as though the action had never been brought”); Bonneville

Associates, Ltd. Partnership v. Baram, 165 F.3d 1360, 1364 (Fed. Cir. 1999)

(“The rule in the federal courts is that ‘[t]he effect of a voluntary dismissal

without prejudice pursuant to Rule 41(a) is to render the proceedings a

nullity and leave the parties as if the action had never been brought.’”)

(citations and internal quotes omitted.)); Accord, Wright, Miller, Kane, and

Marcus, 9 Federal Prac. & Proc. Civ. § 2367 (3d. ed.) (“[A]s numerous

federal courts have made clear, a voluntary dismissal without prejudice

under Rule 41(a) leaves the situation as if the action never had been filed.”)

(footnote omitted).

As in the Macauto case, we agreed that the dismissal without

prejudice leaves the parties as if the action had never been brought, and

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concluded that Ariosa was not barred from filing its Petition in IPR2013-

00250 under 35 U.S.C. § 315(b). IPR2013-00250, Paper 26, 3. As a result,

we did not address Isis’s arguments (IPR2013-00250, Prelim. Res. 44–46)

regarding joinder in the context of the bar under § 315(b). Id.

C. 35 U.S.C. § 315(c)

Isis also argues the joinder statute only allows joinder of parties, not

joinder of issues. PO Resp. 60 (citing IPR2013-00250, Prelim. Resp. 44–

46).

Ariosa’s Motion for Joinder under 37 C.F.R. § 42.122(b) requested

that proceeding IPR2013-00250, involving the same parties and patent as

IPR2012-00022, be joined with that proceeding. IPR2013-00250, Paper 4.

The Joinder Motion was timely filed within one month after institution of

this trial in accordance with § 42.122(b). Isis opposed the Motion on the

ground that the enabling joinder statute, 35 U.S.C. § 315(c), allows only

joinder of parties, not joinder of issues. IPR2013-00250, Prelim. Resp. 44–

45; IPR2012-00022, Paper 72, 6–8.

The statute governing joinder of inter partes review proceedings,

35 U.S.C. § 315(c), provides:

(c) JOINDER.—If the Director institutes an inter partes review, the Director, in his or her discretion, may join as a party to that inter partes review any person who properly files a petition under section 311 that the Director, after receiving a preliminary response under section 313 or the expiration of the time for filing such a response, determines warrants the institution of an inter partes review under section 314.

In its Response to the Petition, Isis maintains that the language in

§ 315(c) addresses joinder of a “party” to a proceeding, rather than the

IPR2012-00022 Patent 6,258,540

19

situation present in this case, where Ariosa essentially seeks the “joinder” of

additional grounds by the same party. PO Resp. 60.

In addressing that argument previously (IPR2013-00250, Paper 25, 4),

we noted that the Board has allowed routinely joinder of additional grounds

by the same party, citing to Microsoft Corp. v. Proxycann, Inc., Case

IPR2013-00109 (PTAB February 25, 2013) (Paper 15), and the Board has

continued to do so. See, e.g., Samsung Elecs. Co., Ltd. v. Virginia

Innovation Scis., Inc., Case IPR2014-00557, slip. op. at 16 (PTAB June 13,

2014) (Paper 10), and cases cited therein. As we now consider the Joinder

Motion at the Final Decision stage of the two involved proceedings, we take

this opportunity to re-examine this issue.

While the plain language of the statute mentions joinder of “a party”

and does not specifically articulate the joinder of issues, it states that “any

person who properly files a petition under section 311” may be joined at the

Director’s discretion. Thus, there does not appear to be any language in the

statute directly prohibiting the joinder of issues by the same party.

The legislative history of this section provides little guidance as to the

scope of this statutory section. As the final Committee Report noted, under

§§ 315(c) and 325(c), “[t]he Director may allow other petitioners to join an

inter partes or post-grant review.” See H.R. Rep. No. 112-98, pt.1, at 76

(2011). During the Senate’s March 2011 debates on the AIA, Senator Kyl

stated that the USPTO expected to allow liberal joinder of reviews:

The Office anticipates that joinder will be allowed as of right—if an inter partes review is instituted on the basis of a petition, for example, a party that files an identical petition will be joined to that proceeding, and thus allowed to file its own briefs and make its own arguments. If a party seeking joinder also presents additional challenges to validity that satisfy the

IPR2012-00022 Patent 6,258,540

20

threshold for instituting a proceeding, the Office will either join that party and its new arguments to the existing proceeding, or institute a second proceeding for the patent.

157 Cong. Rec. S 1376 (daily ed. Mar. 8, 2011) (statement of Sen. Kyl).

Senator Kyl, thus, contemplated the joinder of issues as well as the joinder

of parties.

In addition to noting that §§ 315(c) and 325(c) give the USPTO

discretion over whether to allow joinder, Sen. Kyl observed that “[t]his

safety valve will allow the Office to avoid being overwhelmed if there

happens to be a deluge of joinder petitions in a particular case.” Id. The

Board will determine whether to grant joinder on a case-by-case basis,

taking into account the particular facts of each case, substantive and

procedural issues, and other considerations. See 157 Cong. Rec. S1376

(daily ed. Mar. 8, 2011) (statement of Sen. Kyl) (when determining whether

and when to allow joinder, the Office may consider factors including “the

breadth or unusualness of the claim scope” and claim construction issues).

These remarks highlight the discretion given to the USPTO in joinder

matters. 35 U.S.C. § 315(c). We, thus, conclude that there is nothing in the

language of the statute governing joinder, 35 U.S.C. § 315(c), nor does there

appear to be anything in the legislative history, which limits joinder to the

joinder of parties only.

We also look to our rule that governs joinder in inter partes review,

37 C.F.R. § 42.122, which states:

Request for joinder. Joinder may be requested by a patent owner or petitioner. Any request for joinder must be filed, as a motion under § 42.22, no later than one month after the institution date of any inter partes review for which joinder is

IPR2012-00022 Patent 6,258,540

21

requested. The time period set forth in § 42.101(b) shall not apply when the petition is accompanied by a request for joinder.

The policy basis for construing our rules for governing these

proceedings, which were prescribed as mandated by 35 U.S.C. § 316, is set

forth in the Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,758

(Aug. 14, 2012): “The rules are to be construed so as to ensure the just,

speedy, and inexpensive resolution of a proceeding.” See also 37 C.F.R.

§ 42.1(b) (the rules “shall be construed to secure the just, speedy, and

inexpensive resolution of every proceeding.”). We concluded that under the

present circumstances, that policy was best served by granting Ariosa’s

Motion for Joinder, which resulted in the joinder of this proceeding with

IPR2013-00250. The proceedings involve the same patent and parties, and

there is significant overlap in the asserted prior art, as well as the experts

relied upon. Ariosa was diligent and timely in filing the Motion, such that

there has been no discernible prejudice to either party.

Moreover, while Ariosa is not barred under 35 U.S.C. § 315(b), if

Ariosa had been barred, and if joinder of the same party were not allowed,

the panel would not have the discretion to address the patentability of the

additional claims challenged in IPR2013-00250 (i.e., those which are

dependent on the independent claims challenged in IPR2012-00022, on

which trial already had been instituted). One of the purposes of the AIA was

to “limit unnecessary and counterproductive litigation costs.” 157 Cong.

Rec. S1349 (daily ed. March 8, 2011) (statement of Sen. Leahy). Thus, even

if the independent claims were to be found unpatentable in this proceeding,

by not having the ability to join the dependent claims, the case would have

to go back to the district court for a determination of validity as to those

IPR2012-00022 Patent 6,258,540

22

dependent claims, which would be a waste of judicial resources, and would

increase the litigation costs to both parties.

Isis asserts further that Ariosa should not “have a second bite of the

apple for claim 8.” PO Resp. 60. As set forth in 35 U.S.C. § 325(d), “[i]n

determining whether to institute or order a proceeding under this chapter,

chapter 30, or chapter 31 [chapter providing for inter partes review], the

Director may take into account whether, and reject the petition or request

because, the same or substantially the same prior art or arguments previously

were presented to the Office.” Thus, again, it was at our discretion as to

whether Ariosa should be able to present substantially the same arguments

and prior art as those presented in IPR2012-00022. We conclude it was

appropriate use of our discretion to institute Ariosa’s anticipation challenge

as to claim 8 for the same policy and efficiency considerations discussed

above with respect to exercising our discretion to allow joinder under 35

U.S.C. § 315(c).

D. Claim Construction

In an inter partes review, claim terms in an unexpired patent are

interpreted according to their broadest reasonable construction in light of the

specification of the patent in which they appear. 37 C.F.R. § 100(b); Office

Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766 (Aug. 14, 2012).

Claim terms are also given their ordinary and customary meaning, as would

be understood by one of ordinary skill in the art in the context of the entire

disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.

2007). If an inventor acts as his or her own lexicographer, the definition

must be set forth in the specification with reasonable clarity, deliberateness,

IPR2012-00022 Patent 6,258,540

23

and precision. Renishaw PLC v. Marposs Societa’ per Azioni, 158 F.3d

1243, 1249 (Fed. Cir. 1998).

1. “Detecting” Claim 1 comprises two steps, an amplification step, and a detecting

step, wherein a paternally inherited nucleic acid is amplified, and its

presence is detected. In the Decision to Institute, we construed the

amplification step as including “a step of amplifying nucleic acid from a

serum or plasma sample from a pregnant female, such as by PCR. The

amplified nucleic acid would necessarily include fetal nucleic acid, and the

fetal nucleic acid necessarily includes paternally inherited nucleic acid.”

Dec. Institute, 7–8.

That interpretation is consistent with the construction given that step

by the Court of Appeals for the Federal Circuit in Aria Diagnostics, Inc. v.

Sequenom, Inc., 726 F.3d 1296, 1303 (Fed. Cir. 2013), where the Court

stated:

[T]he claim language requires “amplifying” paternally inherited nucleic acid, without any mention of an effect on the quantity of other nucleic acid. Thus, the claim as written stands infringed without regard to whether, or not, other nucleic acid is amplified. A party that amplifies paternally inherited nucleic acid satisfies this claim limitation without regard to amplification beyond other nucleic acid. The claim does not state that paternally inherited nucleic acid is “selectively” or “only” amplified.

Id.

We acknowledge that in district court, the principles set forth in

Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir. 2005) govern claim

construction, and that would have been the standard applied by the Federal

IPR2012-00022 Patent 6,258,540

24

Circuit in the Aria Diagnostics case, discussed above. In inter partes

review, the claim construction standard is set forth in 37 C.F.R. § 42.100(b),

which states that “[a] claim in an unexpired patent shall be given its broadest

reasonable construction in light of the specification of the patent in which it

appears.” The use of the standard set forth in Phillips is regarded to result in

a narrower construction than the use of the broadest reasonable

interpretation standard. See, e.g., In re Rambus, Inc., 753 F.3d 1253, 1255–

56 (Fed. Cir. 2014) (noting that broadest reasonable interpretation standard

is justified, in part, by the ability to amend the claims, whereas claims in an

expired patent are subject to the claim construction principles in Phillips as

amendments can no longer be made). Thus, we find it incongruous to adopt

a narrower construction in this proceeding, wherein the claims are construed

using the broadest reasonable interpretation standard, than was adopted in

Aria Diagnostics, in which a narrower, Phillips construction standard

applied.

We then interpreted the “detecting” step of claim 1 as not requiring

that the nucleic acid specifically is identified as being inherited from the

father or even as being from the fetus, only that it be identified as containing

some level of nucleic acid. Dec. Institute 8. As noted by Ariosa in its

Reply, that interpretation was consistent with the interpretation of the

Declaration of Dr. Mark I. Evans (Ex. 1033), Isis’s expert in the co-pending

case before the Northern District of California. Reply, 4 (citing Paper 24, 8

(Dec. Institute); Ex. 1033, ¶ 95; Ex. 2223, 9).

Isis contends that “detecting” requires that one determine that the

“detected paternally inherited nucleic acid of fetal origin . . . is not possessed

by the pregnant female.” PO Resp. 15. Specifically, Isis argues that one

IPR2012-00022 Patent 6,258,540

25

cannot “detect the presence of paternally inherited nucleic acid of fetal

origin,” as required by claim 1, without doing that determination. Id.

According to Isis, the whole point of the Specification is to identify

paternally inherited nucleic acid of fetal origin, and that determining step

must be performed in order to determine a fetal or maternal construction

based on paternally inherited nucleic acid of fetal origin. Id. (citing Ex.

1001, 1:6–10; 2:6–18).

Notably, however, Isis does not appear to contest the interpretation of

the amplification step in the Institution Decision. Both the amplification

step and the detecting step of claim 1, however, use very similar language.

That is, the amplifying step requires “amplifying a paternally inherited

nucleic acid from the serum or plasma sample,” and the detecting step

requires “detecting the presence of a paternally inherited nucleic acid of fetal

origin in the sample.” Applicants could have added “only,” such that the

claim read as “only detecting the presence of a paternally inherited nucleic

acid of fetal origin in the sample,” but they chose not to do so. See, e.g.,

Aria, 726 F.3d at 1301 (noting as to the claim limitation of “paternally

inherited nucleic acid” that during prosecution before the examiner the

inventors could have limited the claims to those nucleic acids that were

known in advance to come from the father). Thus, when the “detecting” step

is construed in conjunction with the use of “comprising” as the transitional

phrase, there is nothing in the language of claim 1 that limits the detecting

step to also determining or identifying the detected nucleic acid as being of

fetal origin and not being possessed by the pregnant female.

In addition, as to Isis’s contention that any other interpretation is

inconsistent with the Specification, the Specification specifically states that

IPR2012-00022 Patent 6,258,540

26

the examples “do not in any way limit the scope of the invention.” Ex.

1001, col. 4, ll. 13–14; see also Aria Diagnostics, 726 F.3d at 1301 (noting

the same). Moreover, almost all of the examples perform a PCR

amplification using primers that are specific to the Y chromosome, to

specifically detect fetal DNA. Ex. 1001, col. 5, ll. 6–26 (Example 1, using

primers designed to amplify a single copy Y sequence); col. 6, l. 60–col. 7, l.

3 (Example 2, using SRY specific primers); col. 12, ll. 24–38 (Example 4,

using SRY specific primers); col. 15, ll. 18–48 (Example 5, using SRY

specific primers). The remaining example, Example 3, uses primers specific

for the RhD gene in women known to be RhD negative. Id. at col. 10, ll.

39–51. Thus, the examples are limited to the amplification and detection of

fetal sequences that are known not to be possessed by the pregnant female.

That limitation, however, also was not added to the claims during

prosecution by Applicants, and we decline to read the claim language that

narrowly. See also Aria Diagnostics, 726 F.3d at 1301 (noting that “even if

a specification has only one embodiment, its claims will not be confined to

that example ‘unless the patentee has demonstrated a clear intention to limit

the claim scope using words or expression of manifest exclusion or

restriction.’” (quoting Liebel–Flarsheim Co. v. Medrad, Inc., 358 F.3d 898,

906 (Fed. Cir. 2004)).

Thus, we decline to interpret the “detecting” step as narrowly as

advocated by Isis. Instead, we interpret “detecting” as we did on institution,

that is, as not requiring that the nucleic acid that is isolated from the plasma

or serum of the pregnant female be specifically identified as being inherited

from the father or even as being from the fetus; rather, only that it be

IPR2012-00022 Patent 6,258,540

27

identified as containing some level of nucleic acid, which would include

nucleic acid from the fetus that was inherited from the father.

E. Patentability of the Original Claims

To prevail on its challenges to the patentability of claims, Petitioner

must establish facts supporting its challenges by a preponderance of the

evidence. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).

1. Anticipation of claims 1, 2, 4, 5, 8, 19, 20, 24, and 25 by Kazakov

In order for a prior art reference to serve as an anticipatory reference,

it must disclose every limitation of the claimed invention, either explicitly or

inherently. In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997). We must

analyze prior art references as a skilled artisan would. See Scripps Clinic &

Res. Found. v. Genentech, Inc., 927 F.2d 1565, 1576 (Fed. Cir. 1991),

overruled on other grounds by Abbott Labs. v. Sandoz, Inc., 566 F.3d 1282

(Fed. Cir. 2009) (to anticipate, “[t]here must be no difference between the

claimed invention and the reference disclosure, as viewed by a person of

ordinary skill in the field of the invention”).

A single prior art reference that discloses, either expressly or inherently, each limitation of a claim invalidates that claim by anticipation. Thus, a prior art reference without express reference to a claim limitation may nonetheless anticipate by inherency. “Under the principles of inherency, if the prior art necessarily functions in accordance with, or includes, the claims limitations, it anticipates.” Moreover, “[i]nherency is not necessarily coterminous with knowledge of those ordinary skill in the art. Artisans of ordinary skill may not recognize the inherent characteristics or functioning of the prior art.”

IPR2012-00022 Patent 6,258,540

28

Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1375–76 (Fed. Cir.

2005) (citations omitted). In addition, “[i]t is a general rule that merely

discovering and claiming a new benefit of an old process cannot render the

process again patentable.” In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir.

1990); see also Perricone, 432 F.3d at 1377–78 (noting that the realization

of a new benefit of an old process does not render that process patentable);

Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc., 246 F.3d 1368,

1376 (Fed. Cir. 2001) (stating in the context of a claimed process that was

drawn to the same use comprising the same steps of the prior art, “[n]ewly

discovered results of known processes directed to the same purpose are not

patentable because such results are inherent.”).

We acknowledge:

Inherency, however, may not be established by probabilities or possibilities. The mere fact that a certain thing may result from a given set of circumstances is not sufficient. [Citations omitted.] If, however, the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient.

In re Oelrich, 666 F.2d 578, 581 (CCPA 1981) (quoting Hansgirg v.

Kemmer, 102 F.2d 212, 214 (CCPA 1939)) (emphasis and bracketed

material in original).

Because inherency places subject matter in the public domain as well as an express disclosure, the inherent disclosure of the entire claimed subject matter anticipates as well as inherent disclosure of a single feature of the claimed subject matter. The extent of the inherent disclosure does not limit its anticipatory effect. In general, a limitation or the entire invention is inherent and in the public domain if it is the

IPR2012-00022 Patent 6,258,540

29

‘natural result flowing from’ the explicit disclosure of the prior art.

Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1379 (Fed. Cir.

2003).

Ariosa contends that Kazakov anticipates the claimed methods

because Kazakov inherently detected paternally inherited nucleic acid of

fetal origin. Pet. 43–48; Reply 3–7. According to Ariosa, Kazakov

amplified the DNA in serum that was obtained from pregnant women in

their first and third trimesters of pregnancy. Pet. 43–44. One set of primers

used by Kazakov were the B1 and C1 primers, which Ariosa asserts amplify

sequences throughout the human genome, including sequences unique to the

Y chromosome. Id. at 44 (citing Ex. 1006 (Kazakov Decl.) ¶¶ 11, 26).

Ariosa then relies on the Declarations of Dr. Elaine S. Mansfield and Dr.

Vasily Ivanovich Kazakov to show that inter-Alu sequences were also

amplified, as Alu repeats are present everywhere in the human genome. Id.

at 44–45 (citing Ex. 1007 (Mansfield Decl.) ¶¶ 46, 51–69; Ex. 1006

(Kazakov Decl.) ¶¶ 20–22).

The Kazakov reference teaches that it is known that extracellular

DNA is contained in the blood of humans and animals. Ex. 1014, 232.

According to Kazakov, the “level of extracellular DNA increases in the

blood of women during pregnancy.” Ex. 1014, Abstract. Kazakov studied

the sera from blood of women in both the first and third trimesters of

pregnancy, as well as women with late toxicosis of pregnancy. Id. at 233.

Kazakov then performed PCR using DNA preparations from the serum

using primers for Alu repeats. Id. The primers used by Kazakov were the

IPR2012-00022 Patent 6,258,540

30

Tc65, B1, and C2 primers. Id. Kazakov then detected the DNA using gel

electrophoresis. Id. at Inset VIII.

Kazakov reported that during pregnancy, there is initially an increase

in concentration of low-molecular weight DNA, and that inter-Alu repeats

have been detected only in the blood of women in the first trimester of

pregnancy. Id. at 234. Kazakov notes that both the cells of the fetus

(trophoblasts) and the mother (cells of the endometrium and lymphocytes)

may excrete DNA. Id. at 235.

Kazakov discloses the same method of claim 1. That is, as discussed

above in the section on claim construction, all that is required by the

amplification step of claim 1 is a step of amplifying nucleic acid from a

serum or plasma sample from a pregnant female, such as by PCR, as such

amplified nucleic acid would necessarily include fetal nucleic acid, and the

fetal nucleic acid necessarily includes paternally inherited nucleic acid.

Moreover, as also discussed above, the detecting step does not require that

the detected nucleic acid specifically be identified as being inherited from

the father or even as being from the fetus, only that it be identified as

containing some level of nucleic acid, which would include, necessarily,

nucleic acid from the fetus that was inherited from the father. Here,

Kazakov performs both of those steps: That is, DNA from the serum of

pregnant women is amplified using PCR, and the amplified DNA is detected

using gel electrophoresis, as demonstrated by Figures 1 and 2 of Kazakov.

Moreover, Kazakov specifically notes that the levels of extracellular

DNA increases in the blood of women during pregnancy. Further, as

acknowledged by Isis, “[m]aternal serum and plasma, in vivo, inherently

contain [paternally inherited fetal nucleic acid],” as shown by the ’540

IPR2012-00022 Patent 6,258,540

31

patent. PO Resp. 19. Thus, if the ordinary artisan were to follow the

teachings of Kazakov, and perform PCR on the serum obtained from the

blood obtained from a pregnant female, that blood would inherently contain

paternally inherited fetal nucleic acid. That nucleic acid would be amplified

and detected by the experiments of Kazakov as such a result is necessarily

inherent. That is, the amplification and detection of paternally inherited fetal

nucleic acid would be a new benefit of a known process.

In that regard, we credit the testimony of Dr. Robert Nussbaum11 (Ex.

1215), who states that as of 1995, the techniques used by Kazakov, such as

the serum preparation and PCR, were all conventional. Id. ¶ 17. According

to Dr. Nussbaum:

Although I agree that the Kazakov publication provided to me had very poor reproductions of the data from the PCR experiments conducted, especially the gel reproduced as Figure 2, I find it very difficult to believe that the experiments performed by Kazakov did not amplify and detect any paternally inherited DNA, as the serum samples would contain at least some fetal cell-free DNA and the primers used specifically annealed to human sequences that would have been found in the fetal cell free DNA. I can think of no reason why the 50% of Alus in the fetal genome that are of paternal origin would fail specifically to amplify with these primers. In other words, if any amplification occurred, some of it was perforce paternally derived fetal DNA. Therefore, I believe that Kazakov did amplify some paternally-inherited cell-free DNA, even if it was a very low amount.

Id. ¶ 18.

11 Dr. Nussbaum has worked in the field of medicine, pediatrics, and medical genetics for over 30 years, and is familiar with DNA detection techniques, chromosomal anomalies, and genetic analysis. Ex. 1215 ¶¶ 3–10.

IPR2012-00022 Patent 6,258,540

32

That finding is supported by the Deposition of Dr. Prescott Deininger

(Ex. 1197). When asked “if one were to use cell-free DNA obtained from

serum in a PCR reaction with the B1/C2 primers, would you expect to obtain

amplification products from the fetal cell-free DNA in that sample,” Dr.

Deininger responded that “I would think it would be likely that you would

get some amplification. I do not think it would be likely that it would meet

what I would consider criteria for detection.” Ex. 1197, 122:10–123:7. Dr.

Deininger’s criteria for detection is that one would be able to determine that

the DNA is of fetal origin in some way. Id. at 123:9–12. As construed

above, the claims do not require any recognition that the DNA being

detected is paternally inherited fetal nucleic acid, or even that it is of fetal

origin. As we have declined to adopt Isis’s proposed construction of the

claims, we do not find persuasive Isis’s contention that Kazakov does not

anticipate the claims when the term “detecting” is properly construed. PO

Resp. 14–15.

According to Isis, inherency is a strict doctrine, and “[i]t cannot be

established by mere possibilities or even probabilities.” PO Resp. 16 (citing

In re Rijckaert, 9 F.3d 1531, 1534 (Fed. Cir. 1993)). Isis contends also that

paternally inherited nucleic acid of fetal origin was not necessarily amplified

by Kazakov, and thus Kazakov cannot inherently anticipate the claims. Id.

(citing Ex. 2175 ¶¶ 33–35; Ex. 2127 ¶¶ 44, 51, 60).

Specifically, Isis contends that PCR does not always work, and even if

it does work, amplified product cannot necessarily be detected. PO Resp.

19. Moreover, Isis argues that Kazakov does not provide sufficient details

as to the performance of the experiments, and Isis asserts further that

Kazakov obtained data of poor quality. Id. Thus, Isis contends that the

IPR2012-00022 Patent 6,258,540

33

ordinary artisan would not have concluded that Kazakov necessarily

amplified and detected paternally inherited nucleic acid of fetal origin. Id.

Although the ’540 patent demonstrates that maternal serum and plasma

inherently contains paternally inherited nucleic acid of fetal origin, Isis

argues that Kazakov’s samples “likely” contained little or no paternally

inherited nucleic acid of fetal origin. Id. at 19–20.

Isis contends further that Kazakov “failed to amplify [cell-free] DNA

using TC65 primer in at least one of the samples from first trimester

pregnant women.” PO Resp. 18. In fact, Isis asserts, Dr. Kazakov himself

could not confirm whether the lanes in Figure 2 of Kazakov, which

corresponded to those samples, contained detectable bands. Id. at 18–19

(citing Ex. 2113, 210:4–17).

Isis’s position is, thus, that, even though fetal DNA is necessarily

present in maternal serum, as there may have been experimental errors in

some or all the results reported by Kazakov, whether due to errors in the way

the PCR reaction was performed, contamination, or something else,

Kazakov cannot, under the law of inherency, anticipate the claimed method.

We do not read the doctrine of inherency so strictly. We find the

Federal Circuit’s decision in SmithKline Beecham Corp. v. Apotex Corp.,

403 F.3d 1331 (Fed. Cir 2005) to be instructive. The claims at issue in that

case were drawn to paroxetine hydrochloride [“PHC”] hemihydrate. Id. at

1334. In finding that the claims were inherently anticipated, the Federal

Circuit noted that the district court used a too exacting standard in

determining that the claims were not anticipated. Id. at 1343. According to

the court, all that is required is that the claimed product is the “‘natural result

flowing from the operation as taught [in the prior art].’” Id. (alteration in

IPR2012-00022 Patent 6,258,540

34

original). The district court did not take into account that the prior art does

not require an actual reduction to practice, but only requires an enabling

disclosure. Id. at 1345. Thus, the Federal Circuit held:

[W]hether it was actually possible to make pure PCH anhydrate before the critical date of the . . . patent [at issue] is irrelevant. The [prior art] patent suffices as an anticipatory prior art reference if it discloses in an enabling manner the production of PHC hemihydrate. The [prior art] patent discloses a method of manufacturing PHC anhydrate that naturally results in the production of PHC hemihydrate. Consequently, applying the facts as found by the district court to the correct standard, this court holds that claim 1 of the . . . patent [at issue] is invalid for anticipation by the [prior art] patent.

Id. at 1344 (citations omitted).

Moreover, in King Pharmaceuticals, Inc. v. Eon Labs, Inc., 616 F.3d

1267 (Fed. Cir. 2010), the Federal Circuit held that “[t]o anticipate, the prior

art need only meet the inherently disclosed limitation to the extent the

patented method does.” Id. at 1276. In that case, the claim at issue was

drawn to a method of increasing the bioavailability of the therapeutic,

metaxolone, by administering it with food. Id. at 1274. The patent owner,

King, argued that the prior art’s disclosure of taking metaxalone with food to

reduce gastric discomfort was too vague as to the condition under which the

food was administered, and thus the district court erred in finding that an

increase in bioavailability was “necessarily disclosed.” Id.

The Federal Circuit noted that while the written description of the

patent at issue disclosed specific conditions for food consumption, the

claims only recited taking metaxalone “with food,” and that “[i]t would be

improper to limit the broad terms used in the . . . patent’s claims to the

specific food conditions disclosed in the written description.” Id. at 1275.

IPR2012-00022 Patent 6,258,540

35

The court concluded, that given the broad disclosure of the patent, an

increase in bioavailability of metaxolone naturally occurs when taken with

food. Id. That is, according to the Federal Circuit, the “prior art methods in

their ‘normal and usual operation . . . perform the function which [King]

claims,’” then the patent “‘will be considered, to have been anticipated by

the [prior art].’” Id. at 1275–76 (alterations in original).

The above cases do not support Isis’s position that because

experimental mistakes may have been made by Kazakov, Kazakov cannot

anticipate the claimed methods. The natural result that flows from

amplifying nucleic acid in the serum of blood obtained from a pregnant

woman is that fetal nucleic acid, which both parties agree would inherently

be present, would be amplified, which would include nucleic acid that the

fetus inherited from the father. The ’540 patent does not specify any

conditions under which the amplification or detection steps need be

practiced, such as particular Mg2+ levels, and we decline to read such

limitations into the claim.

We do not find Perricone to be inconsistent with our finding of

inherent anticipation. In that case, the Federal Circuit found that claims

directed to treatment of sunburn were not inherently anticipated, as the prior

art did not teach application to sunburn. Perricone, 432 F.3d at 1378–79.

According to the court, “there is an important distinction between topical

application to skin for the purpose of avoiding sunburn, and the much

narrower topical application to skin sunburn.” Id. at 1379. In contrast,

Kazakov clearly discloses performing an amplification reaction, PCR, on the

nucleic acid from serum obtained from pregnant woman, and then detects

the results of that reaction using gel electrophoresis. Thus, Kazakov teaches

IPR2012-00022 Patent 6,258,540

36

performing PCR on a sample of serum obtained from a pregnant woman,

which necessarily includes an amplification and a detection step, and thus

teaches the method steps specified by claim 1 of the ’540 patent.

Based on the above, whether or not Dr. Mansfield in fact exactly

duplicated the experiments in the Kazakov reference is irrelevant to the

analysis. Isis does not dispute that it was well within the level of the skilled

artisan to perform an amplification reaction properly, such as by PCR, on a

serum sample obtained from the blood of a pregnant female. In fact,

according to Isis, the level of the person ordinary skill in the art

would . . . have had knowledge and skill about the principles and use of amplification and detection techniques for fetal nucleic acids from maternal blood, e.g., polymerase chain reaction (PCR). This includes knowledge and skill about the equipment, processes and techniques for isolating nucleic acids from biological samples and analyzing the isolated or amplified nucleic acids.

Mot. to Amend 4. Thus, the ordinary artisan, following the teachings of

Kazakov, would amplify and detect the nucleic acid contained in the serum

sample obtained from a pregnant woman. The fact that the artisan may not

have appreciated that paternally inherited nucleic acid from the fetus was

part of the nucleic acid being amplified and detected is irrelevant to the

analysis, because the claim as construed herein does not require a step of

identifying the source of the nucleic acid.

We have considered Isis’s arguments that the testimony of Dr.

Mansfield is not reliable, as well as the arguments that the Kazakov

reference provides insufficient detail as to the conditions of the amplification

reaction. See PO Resp. 16–29. We do not find those arguments convincing,

however, for the reasons set forth above.

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37

We conclude, therefore, that Ariosa has demonstrated by a

preponderance of the evidence that claim 1 is anticipated under 35 U.S.C.

§ 102(b) by Kazakov. Isis presents no additional arguments as to claims 2,

19, and 20, other than those discussed above as to claim 1. Based on our

review of the evidence presented by Ariosa, we conclude that Ariosa has

established by a preponderance of the evidence that Kazakov anticipates

those claims as well.

Isis contends further, without providing additional argument,12 that

Kazakov does not meet the limitations of claims 4, 5, 8, 24, or 25. PO Resp.

29. We have reviewed those claims, as well as the evidence presented by

Ariosa, and determine that the preponderance of the evidence of record

demonstrates that those claims are anticipated by Kazakov as well.

2. Obviousness of Claims 1, 2, 4, 5, 19–22, 24, and 25 over the Combination of Simpson, Schallhammer, and Kazakov

A claim is unpatentable under 35 U.S.C. § 103(a) if the differences

between the claimed subject matter and the prior art are such that the subject

matter, as a whole, would have been obvious at the time the invention was

made to a person having ordinary skill in the art to which said subject matter

pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). The

question of obviousness is resolved on the basis of underlying factual

determinations including: (1) the scope and content of the prior art; (2) any

differences between the claimed subject matter and the prior art; (3) the level 12 We note that Isis cites Exhibit 2161, ¶¶ 34–77, but provides no argument in the Patent Owner response. PO Resp. 29. Isis’s citation to Exhibit 2161, therefore, amounts to improper incorporation by reference, and we thus decline to consider the cited paragraphs of that Exhibit in this context. See 37 C.F.R. 42.6(a)(3).

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of skill in the art; and (4) where in evidence, so-called secondary

considerations. Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966). The

level of ordinary skill in the art usually is evidenced by the references

themselves. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir.

2001); In re GPAC Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); In re Oelrich,

579 F.2d 86, 91 (CCPA 1978).

For an obviousness analysis, prior art references must be “considered

together with the knowledge of one of ordinary skill in the pertinent art.” In

re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994) (quoting In re Samour, 571

F.2d 559, 562 (CCPA 1978)). Moreover, “it is proper to take into account

not only specific teachings of the reference but also the inferences which one

skilled in the art would reasonably be expected to draw therefrom.” In re

Preda, 401 F.2d 825, 826 (CCPA 1968). That is because an obviousness

analysis “need not seek out precise teachings directed to the specific subject

matter of the challenged claim, for a court can take account of the inferences

and creative steps that a person of ordinary skill in the art would employ.”

KSR, 550 U.S. at 418; see also In re Translogic Tech., Inc., 504 F.3d. at

1259.

As an initial matter, we note that Isis contends that Schallhammer is

not prior art. PO Resp. 30. Ariosa, in response, does not argue Isis’s

contention that Schallhammer is not prior art to the claims, but argues that,

although the trial was instituted on the combination of Simpson,

Schallhammer, and Kazakov, we only expressly relied on the teachings of

Simpson and Kazakov to institute trial. Reply 8–9. As we agree that the

teachings of Schallhammer are cumulative to those of Simpson and

Kazakov, we conclude that Ariosa’s failure to continue to rely on

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Schallhammer in arguing the challenge, in and of itself, is not fatal to the

obviousness challenge. Thus, we only address the challenge further to the

extent that it relies on Simpson and Kazakov.

Ariosa contends that the combination of Simpson and Kazakov

renders obvious claims 1, 2, 4, 5, 8, 19–22, 24, and 25 of the ’540 patent.

Pet. 49–52; Reply 9. According to Ariosa, Simpson teaches that fetal cells,

or at least fetal DNA, are present in maternal blood. Pet. 49.

Specifically, Simpson teaches that fetal cells may be recovered from

maternal blood, and that various chromosomal abnormalities, such as

trisomies, have been detected using fetal cells. Ex. 1025, Abstract.

According to Simpson, Lo demonstrated that “fetal cells, or at least fetal

DNA, indeed existed in maternal blood.” Id. at 1230, col. 1. Simpson

teaches that the sensitivity required in making that demonstration was

achieved by using nested PCR to amplify for Y sequences, and women that

were carrying a male fetus were more likely to show a Y-chromosome

specific signal. Id. at 1230, paragraph bridging the cols. The sample used

was unsorted nucleated cells. Id.

Ariosa relies on Kazakov as demonstrating that the levels of

extracellular DNA increases in the blood of pregnant females. Pet. 50

(citing Ex. 1007 (Mansfield Decl.) ¶ 95). The teachings of Kazakov are

discussed above.

Isis responds that Kazakov in combination with Simpson does not

render obvious the claimed methods, as Kazakov does not teach that cell-

free DNA of fetal origin increases in pregnancy, but teaches only that there

is increased cell-free DNA in the first trimester. PO Resp. 42 (citing Ex.

2175 ¶ 34). And although Dr. Kazakov relies on the disclosure at page 234

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of the Kazakov reference in his Declaration to support the obviousness

challenge. (id. (citing Ex. 2127 ¶¶ 72–73)), that paragraph discusses

maternal cells, not fetal cells.

Isis argues further that a person of ordinary skill in the art would not

have had a reasonable expectation of success of detecting paternally

inherited fetal nucleic acid in the serum or plasma obtained from a pregnant

female. Id. (citing Ex. 2127, ¶¶ 100–109; Ex. 2175 ¶¶ 63–65; Ex. 2161

¶¶ 114–119). Isis argues that the prior art, such as Simpson, taught

examining the DNA in isolated fetal cells, and routinely discarded the cell-

free portion of the blood, i.e., the plasma and the serum. PO Resp. 37 (citing

Ex. 2175 ¶¶ 66, 68; Ex. 2127 ¶ 100, 101). Simpson relies on two Lo papers

in making the statement that fetal DNA was found in maternal blood. Id. at

38. Those papers, according to Isis, used whole blood to detect DNA, and

thus the ordinary artisan would have understood that the source of the

detected DNA was fetal cells, and not plasma or serum. Id. (citing Ex. 2127

¶¶ 89–93).

Isis contends further that the prior art taught that “fetal cells were

vanishingly rare and not present in all pregnant women.” PO Resp. 38

(citing Ex. 2127 ¶¶ 103–104; Ex. 2175 ¶ 73; Ex. 2185 ¶¶ 28–31). Because

those cells were so rare in maternal blood, Isis argues that the ordinary

artisan “would have expected that DNA released from such cells would also

have been rare, if it existed at all.” Id. at 39 (citing Ex. 2127 ¶¶ 103–104;

Ex. 2175 ¶ 64).

The primary focus of Simpson, as discussed above, is the analysis of

DNA from fetal cells isolated from maternal blood. Ex. 1025, Abstract. In

determining that Ariosa had established a reasonable likelihood that the

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41

combination of Simpson and Kazakov would have rendered obvious the

claimed methods, we noted that “Simpson suggests that the DNA would be

found in levels sufficient to be determined using amplification reactions,

such as PCR, by teaching that Y specific signals were seen in women

carrying a male fetus (Simpson 1230, bridging ¶).” Dec. Institute 31.

The paragraph we relied upon in the Simpson reference cited to two

papers by Lo. As noted by Isis’s expert, Dr. Robert Williamson,13 it was the

cellular component of maternal blood that contained fetal DNA. Ex. 2127

¶¶ 89–93. The Lo 199014 article states that blood samples from pregnant

females were analyzed, but does not discuss using only the serum or plasma

from the samples. Ex. 1044, 1463. Lo 198915 discusses the use of PCR to

detect male fetal cells, in which PCR was extracted from the blood samples.

Ex. 1045, 1363–64. Moreover, Simpson states that the work of Lo was

performed on unsorted nuclear cells. Ex. 1025, 1230, col. 2. Thus, the

preponderance of evidence supports a finding that when Simpson reported

that Lo demonstrated that fetal DNA could be found in maternal blood (id. at

col. 1), the source of that DNA would have been understood by the ordinary

artisan to be fetal cells, and not cell-free DNA.

In addition, the preponderance of evidence of record supports a

finding that the presence of fetal cells in maternal blood is a rare occurrence.

13 Dr. Williamson is an expert in the fields of molecular biology and molecular genetics (Ex. 2127 ¶¶ 6–16), and based on his credentials, which do not appear to be contested by Ariosa, we consider him competent to testify as to the subject matter in his Declaration. 14 Lo et al., Detection of Single-Copy Fetal DNA Sequence from Maternal Blood, 335 LANCET 1463–64 (1990) (Ex. 1044). 15 Lo et al., Prenatal Sex Determination by DNA Amplification from Maternal Peripheral Blood, 2 LANCET 1363–65 (Ex. 1045).

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As testified by Dr. Williamson, “fetal cells in maternal blood were a scarce

commodity.” Ex. 2127, ¶ 103. That is supported by the Bianchi reference,

relied upon by Ariosa, which teaches that “[f]etal cells are rare in the

maternal circulation; all current methods used for their isolation also yield

maternal cells.” Ex. 1043,16 Abstract.

Moreover, as noted by Isis, although Kazakov teaches that the “level

of extracellular DNA increases in the blood of women during pregnancy,”

(Ex. 1014, Abstract), Kazakov concludes:

Thus, in the early stages of pregnancy in humans, cells of the fetus (trophoblasts) and the mother (cells of the endometrium and lymphocytes) may excrete DNA. In view of the above, and also considering the transposonic and recombinogenic nature of the Alu repeats, it can be conjectured that the inter-Alu repeats discovered by us in the blood serum of pregnant women may play some kind of regulatory role in the early stages of pregnancy. The cloning and sequencing of these fragments is of particular interest. What has been said does not rule out the presence of other inter-Alu repeats in the blood of pregnant women, which can be identified by means of other primers and may have their own features of distribution in the blood in the course of pregnancy.

Id. at 235 (citation omitted). Thus, it is clear that Kazakov does not consider

fetal DNA to be the only source of the increased DNA in maternal serum

during the first trimester, but also considers maternal sources, and does not

rule out the possibility that the DNA being amplified is only from maternal

sources. That position is supported by the testimony of Dr. Williamson,

who states that, as set forth by the Kazakov reference, the origin of the

extracellular DNA “is completely left to conjecture.” Ex. 2127 ¶ 97.

16 All references to Ex. 1043 are to the exhibit as filed in IPR2013-00250.

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43

Based on the above, we conclude that the ordinary artisan would not

have used the serum sample of Kazakov, which is a cell-free sample, for the

whole blood sample of Simpson, which contains the cellular fraction, for the

analysis of fetal DNA as taught by Simpson. The ordinary artisan would not

have had a reasonable expectation that the fetal DNA would have been

present in maternal serum in sufficient quantities for detection using

amplification methods such as PCR given the understanding in the art that

fetal cells were a rare occurrence in maternal blood. Moreover, Kazakov’s

lack of teaching that the increase in extracellular DNA in the serum of

pregnant females is due to the presence of cell-free fetal DNA in the serum

further supports that conclusion.

We have considered Ariosa’s arguments in response, but they do not

persuade us otherwise. Ariosa argues that the experts agree “that techniques

taught in Simpson would have successfully amplified [cell-free] DNA in the

maternal serum as suggested by Kazakov.” Reply 8 (citing Ex. 1200 ¶ 67;

Ex. 1215 ¶¶ 42–43). According to Ariosa, the “explicit suggestion by

Kazakov that maternal serum may contain fetal DNA cannot be overcome

by a generalized belief . . . that fetal DNA was not present in appreciable

quantities in maternal serum or plasma.” Id. (citing Ex. 1200, ¶¶ 63–64).

Ariosa contends that Isis’s arguments, such as those based on the

Declaration testimony of Dr. Fisk, are “premised upon the erroneous belief

that the term ‘detect’ requires [paternally inherited fetal nucleic acid] to be

distinctly distinguished from maternal DNA.” Id. at 12.

Kazakov, Ariosa contends, specifically states that there are two

potential sources of cell-free DNA, that is, fetal and maternal. Id. at 13

(citing Ex. 1014). Ariosa relies on the Declaration of Dr. Nussbaum, who

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44

stated that Kazakov’s results “‘would have been intriguing to a person

working in prenatal diagnosis as it would have signaled that maternal plasma

or serum might be a potential new source for fetal DNA.’” Id. at 14 (quoting

Ex. 1215 ¶¶ 40, 41); see also Ex. 1200 ¶ 64 (Ariosa’s expert, Dr.

Valeri Vasioukhin opining that “researchers in prenatal molecular diagnosis

would have appreciated the implications of the Kazakov results and

incorporated this newly identified source of fetal DNA into existing prenatal

molecular diagnostic techniques.”).

We agree with Ariosa that “detect” as used in the claimed methods

does not require identification of the detected DNA as paternally inherited

DNA, or even as fetal DNA. Simpson, however, analyzes fetal DNA for

purposes of prenatal diagnosis of chromosomal abnormalities. Ex. 1025,

Abstract. Thus, the only reason for one to use the serum of Kazakov in the

method of Simpson would also be to detect fetal chromosomal

abnormalities, which would have required some level of realization that fetal

nucleic acid was in fact being detected.

Moreover, we have considered the evidence cited by Ariosa, but

again, conclude that it does not establish by a preponderance of the evidence

of record that the combination of Simpson and Kazakov would have

rendered obvious the method of the challenged claims. As stated by

Dr. Vasioukhin:

I believe a researcher working in prenatal molecular diagnostics would have a very high expectation of success if the maternal serum samples did indeed contain fetal cell free-nucleic acids, which we now know such serum samples from pregnant women naturally do. The use of the specific primers taught in Simpson 1993 (e.g., the Y1.7 and Y1.8 primers) would have resulted in the amplification and detection of

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paternally inherited nucleic acids if PCR using these primers had been carried out using cell-free DNA template from a pregnant woman.

Ex. 1200 ¶ 67 (footnote omitted).

While we agree with Dr. Vasioukhin that it would have been well

within the level of skill of the ordinary artisan to use the primers of Simpson

on the serum sample of Kazakov, that does not address the question as to

whether the ordinary artisan would have expected there to be sufficient

quantities of cell-free DNA in maternal DNA for the detection of fetal

chromosomal abnormalities as taught by Simpson. That opi